Ligand-receptor interactions and their modulation by antibodies are important for a number of biological processes including virus entry and signal transduction through membranes. Our long-term goal has been the elucidation of the molecular mechanisms of these interactions and the development of antibody-based therapeutics, vaccines and reagents for diagnosis and research.During the fiscal year 2004 we continued our research on the identification and characterization of potent broadly neutralizing human monoclonal antibodies (hmAbs) against HIV-1. We showed that one of the antibodies we developed, m9, has exceptional potency and breadth of neutralization of primary isolates including those from clade C which is the dominant clade around the world where m9 was much better than any other monoclonal antibody available today. We are also developing novel anti-gp41 hmAbs which we selected by a new methodology we developed based on competitive antigen panning. Our results were reported in five articles published in JMB, JIM, Antivural Research, J. Virology and Biochemistry, and reviewed in Nat. Rev. Microbiology. New patent applications were filed for our new anti-gp41 hmAbs, for the cloning of the anti-gp120 hmAb A32 and for the fusion protein scFv-Fc. Two companies (Tanox, Inc and Virosys Pharmaceuticals, Inc) licensed three of our patent applications. More than 30 requests for these antibodies were received and executed through MTAs.We also responded very quickly to the public threat by the SARS epidemics and were the first to express and characterize the function of the SARS-CoV S glycoprotein - we identified the receptor-binding domain and soluble fragments that could be used as inhibitors and vaccines. Four papers were published or accepted for publication - three in BBRC and one in Cell. One patent application was filed and several companies have been interested to license. We are receiving numerous requests for reprints and reagents after the publication of our first paper in November 2003, and that paper has been cited more than 20 times.We also developed novel hmAbs against the Hendra G protein which exhibited potent inhibitory activity against fusion mediated by the envelope glycoproteins of Hendra and Nipah viruses. These antibodies were selected from a new large nave human antibody library we developed from lymphocytes obtained from 10 healthy donors. Patent application is being filed for the antibodies and an invention report for the library that could be a valuable resource of human antibodies.The interactions of the ligands, insulin, IGF-1 and IGF-2, with their receptors that lead to conformational changes and signal transduction across plasma membranes resemble in many ways the interactions of the viral envelope glycoproteins with their receptors leading to conformational changes and transfer of the viral genome across the plasma membrane. By using approaches and reagents similar or identical to those used for characterization of the virus entry mechanisms and development of antibodies modulating them, we have recently began to develop hmAbs against components of the IGF system that are associated with cancer. We have cloned the precursor of IGF-2 and currently are screening our new human antibody library for antibodies against IGF-2 and IGF-1. We have also cloned a mouse antibody that can downmodulate the IGF-1R and are humanizing it with potentical clinical applications for cancer treatment. We are also cloning the extracellular domains of the IGF-1R and insulin receptor variant A for characterization of their interactions with ligands and development of hmAbs. We have also developed a hmAb against another cancer-associated antigen - survivin.Z01 BC 10257-07